Adaptive preconditioning in neurological diseases -­ therapeutic insights from proteostatic perturbations

International audienceIn neurological disorders, both acute and chronic neural stress can disrupt cellular proteostasis, resulting in the generation of pathological protein. However in most cases, neurons adapt to these proteostatic perturbations by activating a range of cellular protective and repair responses, thus maintaining cell function. These interconnected adaptive mechanisms comprise a 'proteostasis network' and include the unfolded protein response, the ubiquitin proteasome system and autophagy. Interestingly, several recent studies have shown that these adaptive responses can be stimulated by preconditioning treatments, which confer resistance to a subsequent toxic challenge - the phenomenon known as hormesis. In this review we discuss the impact of adaptive stress responses stimulated in diverse human neuropathologies including Parkinson´s disease, Wolfram syndrome, brain ischemia, and brain cancer. Further, we examine how these responses - and the molecular pathways they recruit - might be exploited for therapeutic gai

Efficient Pruning Technique Based on Linear Relaxations

This paper extends the Quad-filtering algorithm for handling general nonlinear systems. This extended algorithm is based on the RLT (Reformulation-Linearization Technique) schema. In the reformulation phase, tight convex and concave approximations of nonlinear terms are generated, that’s to say for bilinear terms, product of variables, power and univariate terms. New variables are introduced to linearize the initial constraint system. A linear programming solver is called to prune the domains. A combination of this filtering technique with Box-consistency filtering algorithm has been investigated. Experimental results on difficult problems show that a solver based on this combination outperforms classical CSP solvers